Particle-induced increases in respiratory morbidity and mortality have been observed worldwide in industrialized cities but the toxicologic mechanisms have not been elucidated. It is hypothesized that subpopulations including the elderly and individuals with cardiopulmonary disease are particularly at risk to the effects of exposure. Genetic background is another important host factor that may contribute to interindividual responsivity to particulate exposure. We designed a study to identify susceptibility loci for alveolar macrophage (AM) immune dysfunction induced by inhalation of sulfate-associated carbon particles in susceptible C57BL/6J (B6) and resistant C3H/HeJ (C3) inbred mice. AMs were chosen for study because they represent an important component of host defense, and compromised host defense has been hypothesized to be an important factor in particle-induced respiratory morbidity. Analyses of AM dysfunction phenotypes of segregant populations derived from B6 and C3 progenitors indicated that two unlinked genes control susceptibility. A genome-wide linkage analysis of an intercross (B6C3F2) cohort identified significant and suggestive quantitative trait loci (QTLs) on chromosomes 17 and 11, respectively. Candidate susceptibility genes were identified by comparative mapping and included tumor necrosis factor alpha (Tnf), lymphotoxin alpha (Lta), and monocyte chemoattractant protein 1 (Ccl2). Importantly, both QTLs overlap previously identified susceptibility QTLs for lung injury induced by the common pollutant ozone, as well as bleomycin and radiation. This may suggest common regulatory loci for injury and inflammation in the lung. Because particulate air pollution has many sources, and composition varies regionally, we have expanded our studies to include another particulate called ROFA (residual oil fly ash) which is derived as a combustion product of fuel oil. Among inbred strains of mice, instilled ROFA induced strain-specific lung hyperpermeability and inflammation, with the greatest differences occurring between C3H/HeOuJ (OuJ) and C3 mice. This observation is particularly interesting as these two strains differ only at a polymorphism in the coding region of a gene for Toll-like receptor 4 (Tlr4) which has an important role in innate immunity and responsiveness to bacterial endotoxin and ozone. Differential regulation of TLR4 message levels and TLR4 signaling proteins were consistent with a role for Tlr4 in responsiveness to particulate challenge in the mouse. The effect of particulates on the innnate immune system suggest that one of the toxic outcomes of exposure is compromise of host defense mechanisms.